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Accepted Manuscript
Research Article
Using genetic buffering relationships identified in fission yeast to reveal susceptibilities in cells lacking hamartin or tuberin function
Ashyad Rayhan, Adam Faller, Ryan Chevalier, Alannah Mattice, Jim Karagiannis
Biology Open 2017 : bio.031302 doi: 10.1242/bio.031302 Published 20 December 2017
Ashyad Rayhan
Department of Biology, The University of Western Ontario, London, Ontario, Canada
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Adam Faller
Department of Biology, The University of Western Ontario, London, Ontario, Canada
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Ryan Chevalier
Department of Biology, The University of Western Ontario, London, Ontario, Canada
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Alannah Mattice
Department of Biology, The University of Western Ontario, London, Ontario, Canada
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Jim Karagiannis
Department of Biology, The University of Western Ontario, London, Ontario, Canada
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  • ORCID record for Jim Karagiannis
  • For correspondence: jkaragia@uwo.ca
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Abstract

Tuberous sclerosis complex is an autosomal dominant disorder characterized by benign tumors arising from the abnormal activation of mTOR signaling in cells lacking TSC1 (hamartin) or TSC2 (tuberin) activity. To expand the genetic framework surrounding this group of growth regulators, we utilized the model eukaryote Schizosaccharomyces pombe to uncover and characterize genes that buffer the phenotypic effects of mutations in the orthologous tsc1 or tsc2 loci. Our study identified two genes: fft3 (encoding a DNA helicase) and ypa1 (encoding a peptidyle-prolyl cis/trans isomerase). While the deletion of fft3 or ypa1 has little effect in wild-type fission yeast cells, their loss in tsc1Δ or tsc2Δ backgrounds results in severe growth inhibition. These data suggest that the inhibition of Ypa1p or Fft3p might represent an “Achilles’ heel” of cells defective in hamartin/tuberin function. Furthermore, we demonstrate that the interaction between tsc1/tsc2 and ypa1 can be rescued through treatment with the mTOR inhibitor, torin-1, and that ypa1Δ cells are resistant to the glycolytic inhibitor, 2-deoxyglucose. This identifies ypa1 as a novel upstream regulator of mTOR and suggests that the effects of ypa1 loss, together with mTOR activation, combine to result in a cellular maladaptation in energy metabolism that is profoundly inhibitory to growth.

  • Received November 16, 2017.
  • Accepted December 12, 2017.
  • © 2017. Published by The Company of Biologists Ltd
http://creativecommons.org/licenses/by/3.0

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Keywords

  • Tuberous sclerosis complex
  • Schizosaccharomyces pombe
  • mTOR
  • Genetic buffering
  • Synthetic sickness or lethality (SSL)

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Accepted Manuscript
Research Article
Using genetic buffering relationships identified in fission yeast to reveal susceptibilities in cells lacking hamartin or tuberin function
Ashyad Rayhan, Adam Faller, Ryan Chevalier, Alannah Mattice, Jim Karagiannis
Biology Open 2017 : bio.031302 doi: 10.1242/bio.031302 Published 20 December 2017
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Accepted Manuscript
Research Article
Using genetic buffering relationships identified in fission yeast to reveal susceptibilities in cells lacking hamartin or tuberin function
Ashyad Rayhan, Adam Faller, Ryan Chevalier, Alannah Mattice, Jim Karagiannis
Biology Open 2017 : bio.031302 doi: 10.1242/bio.031302 Published 20 December 2017

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